CCL3 Receptor Antagonists May Help Combat Noonan Syndrome–Associated Leukemia

A new study has found that the CCL3 receptor may be involved in Noonan syndrome–associated leukemias, and CCL3-receptor antagonists could play a role in treating some leukemias. The study, which was published October 26, 2016, in Nature, revealed a critical contribution of Ptpn11 mutations in the bone marrow microenvironment to leukemogenesis. It also identified CCL3 as a potential therapeutic target for controlling leukemic progression in Noonan syndrome and for improving stem cell transplantation therapy in Noonan syndrome–associated leukemias.

Noonan syndrome often involves short stature, distinctive facial features, congenital heart defects, and other problems. It occurs in one in 1,000 to 2,500 people, and can be caused by mutations in several genes. The most common cause is mutations in the Ptpn11 gene. Children with Noonan syndrome are estimated to have an eight times higher risk of developing leukemia than their peers.

The current study suggests that certain DNA mutations in bone cells that support blood development can drive leukemia formation in nearby blood stem cells. Many cancer-driving mutations are “cell-autonomous”, and the changes in a cell's DNA makes that same cell grow more rapidly. In contrast, an indirect neighbor cell effect was observed in a mouse model of Noonan syndrome.

The neighbor cell effect could be frustrating efforts to treat leukemias in patients with Noonan syndrome because bone marrow transplant may remove the cancerous cells, but not the cause of the problem, leading to disease recurrence. However, the researchers show that a class of drugs can dampen the cancer-driving neighbor effect in mice.

"Our research highlights the importance of the bone marrow microenvironment," said study co-author Cheng-Kui Qu, MD, PhD, a professor of pediatrics at Emory University School of Medicine, Winship Cancer Institute,  in Atlanta, Georgia. "We found that a disease-associated mutation, which disturbs the niches where blood stem cell development occurs, can lead to leukemia formation."

Previous research had established that mutations in Ptpn11 have a conventional cell-autonomous effect on the growth of blood stem cells. Qu and colleagues show that Ptpn11 mutations also affect mesenchymal stem cells. The mutations cause the mesenchymal stem cells to overproduce CCL3, which attracts monocytes into the blood stem cells' niches. Consequently, the monocytes make inflammatory molecules that stimulate the blood stem cells to differentiate and proliferate, leading to leukemias.

Dr. Qu's team developed genetically engineered mice that altered PTPN11 in neural cells; all of the mice developed an enlarged spleen and a condition resembling myeloproliferative disorder at an early age. In addition, the mice also had mutated PTPN11 genes in mesenchymal stem cells, but not blood stem cells.  This demonstrated that agents that counteract CCL3 dampen the myeloproliferative disorder in the mutant mice. One of those agents is maraviroc, which has been Food and Drug Administration–approved to combat human immunodeficiency virus infection, and another is BX471, which is under development for multiple sclerosis.